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MC-CIG - Support for training and career development of researcher (CIG)

Ziel

Intestinal epithelial cells (IECs) constitute the primary barrier that enteric pathogens have to face. The mechanism by which innate immunity is regulated in IECs remains unclear. However, it is known that a delicate balance is required to efficiently recognize pathogens and at the same time to not illicit an immune response against the commensal microbial flora. Inappropriate immune response to the commensal flora is suspected to be responsible for inflammatory bowel diseases.We found that IECs could generate a different innate immune response upon viral infection, depending on where the infection originates from (apical vs. basolateral). Moreover, infection of the cells from the apical plasma membrane (gut lumen) renders IECs less responsive to subsequent viral infection. This down-regulation of innate immune response could represent a mechanism developed by IECs to avoid recognition of the commensal flora thereby preventing constant inflammation of the bowel.The objective of this project is to discover the means by which antiviral innate immunity is achieved and regulated in IECs. We will use a multidisciplinary approach, combining live-cell microscopy, single particle/molecule tracking, biochemistry, and genomics. The specific aims are:1) Determine the importance of RLR and TLR in generating an innate immune response in IECsWe will characterize the signaling pathways triggered upon viral infection of IECs from the apical and basolateral sides. We will characterize the mechanism by which apical infection downregulates the innate immune response of subsequent infection.2) Spatio-temporal aspect of viral RNA recognition in IECsWe will develop new tools to study, within a living cell, the spatio-temporal aspect of virus detection by the cellular sensors RLR and TLR. We will determine how signal transduction is initiated or orchestrated upon detection of infection. We will address whether recognition of the pathogen and signal transduction takes place in different sub-cellular compartments depending on the site of virus entry (apical vs basolateral).3) Impact of cellular polarization on signal transduction during innate immune responseWe will characterize the signal transduction pathways of various TLR in polarized IECs and oppose it to the signaling pathways generated by non-polarized IECs. We will determine the location (plasma membrane or endosomal compartment) from where TLRs signal from in polarized IECs and oppose it to non-polarized cells. We will identify and characterize the molecular mechanisms that allow IECs to remodel TLR signaling upon cellular polarization. Ultimately, we will determine the reasons for such TLR signaling remodeling.The long-term goal of the laboratory is to understand how IECs can tolerate the commensal flora (bacteria and viruses) and at the same time efficiently recognize enteric pathogens.